Download Ruboxistaurin`s future in doubt, despite promising study

Diabetes and the Eye
Special Focus
Ruboxistaurin's future in doubt, despite
promising study results
John Lechleiter
Lloyd P Aiello
By Sean Henahan
ANTI-VEGF drugs are producing impressive
initial clinical results in the treatment of
diabetic retinopathy and macular oedema.
However, if these results are confirmed in
larger clinical trials, patients would need to
receive intraocular injections every four to
six weeks for the rest of their lives, a reality
that could limit the usefulness of these
agents.
Ruboxistaurin (Arxxant, Lilly), a drug that is
administered in tablet form and also
produced promising early results, would have
transcended that problem. However, it is now
uncertain whether Eli Lilly will continue to
develop the drug, following a recent FDA
decision mandating three years of additional
clinical trials
Ruboxistaurin mesylate is a specific
inhibitor of PKCß, an enzyme that has been
implicated in retinopathy.The results of a
three-year multicentre clinical trial (PKCDRS 2), first reported at the American
Academy of Ophthalmology scientific
sessions in Chicago, Illinois, recently appeared
in the journal Ophthalmology, (December 2006,
Vol. 113, Issue 12, 2221-2230).
The double-blind study randomised 685
patients at 70 clinical sites to oral
ruboxistaurin (32mg/day) or placebo for 36
months. Inclusion criteria included a bestcorrected visual acuity score of at least 45
letters, retinopathy level of at least 47A and
no more than 53E, and no prior panretinal
photocoagulation in at least one eye.The
study included patients with Type 1 and Type
2 diabetes. Mean age of patients was 59 years.
Exclusion criteria included unstable angina,
systolic blood pressure of 190 mmHg or
diastolic blood pressure of 105 mmHg, a
corrected QT interval of greater than 500
milliseconds, or malignancy within the past
six months.
Patients underwent eye exams at screening
and every three months, and retinopathy
screening every six months. Retinopathy
screening involved Early Treatment Diabetic
Retinopathy Study (ETDRS) standard 7-field
30° colour stereoscopic fundus photography.
Two independent graders determined the
extent of retinopathy and macular oedema.
At three years, patients receiving the test
drug had a 40 per cent risk reduction for
sustained moderate visual loss compared to
those receiving placebo.Vision loss occurred
in 5.5 per cent of those on active treatment
compared with 9.1 per cent in placebotreated patients.The difference was
statistically significant.
Patients on active treatment also had
better mean visual acuity after 12 months.
Ruboxistaurin treatment produced visual
improvement of at least 15 letters and was
more frequent in 4.9 per cent of cases,
compared with 2.4 per cent for placebo.
Patients on placebo were also more likely to
8
lose 15 letters over the course of the trial.
Patients on ruboxistaurin also fared better
with macular oedema.These patients were
less likely to develop progression of oedema
to within 100 µm of the centre of the macula
than placebo recipients.They were also
significantly less likely to require laser
treatment for macular oedema.
Ruboxistaurin also appeared to be well
tolerated, with no reported clinically
significant adverse events or lab
abnormalities. Dropout rates were the same
for active treatment and placebo.
“The results of the current study are the
first to demonstrate that an orally
administered pharmacologic agent
(ruboxistaurin) can be well tolerated and
reduce vision loss in patients with diabetes
over an extended period,” the researchers
said.
The researchers note that the effect of
ruboxistaurin on macular oedema
progression and vision is consistent with the
hypothesis that hyperglycaemia induces
synthesis of diacylglycerol, which activates
PKC in the retina.This mediates vascular
dysfunction and leads to increased vascular
permeability, possibly through alterations in
tight junction structure.
One disappointing result in this study was
that ruboxistaurin did not appear to influence
the progression of non-proliferative diabetic
retinopathy to the proliferative form, nor did
it appear to reduce the need for panretinal
photocoagulation for diabetic retinopathy.
The researchers note that several factors
could account for this lack of effect.Those
factors would include a limited follow-up
time, retinopathy that was already too
severe, insufficient dosing, or activation of
compensatory mechanisms.
In spite of the lack of effect on retinopathy
progression, Lilly had results suggesting
potentially useful therapeutic effects.These
results supported those from an earlier
phase III trial (Diabetes 2005; 54- 2108-97).
Accordingly, the company went ahead and
submitted a new drug application (NDA) to
seek approval from the US Food and Drug
Administration for ruboxistaurin for the
treatment of moderate to severe nonproliferative diabetic retinopathy in February
2006.
Much to the surprise of Lilly, the FDA
responded by issuing an approvable letter, an
indication that the agency wanted more
information.The letter requested that Lilly
submit additional data to support the clinical
evidence from the PKC DR2 study. Lilly
appealed the decision, hoping that it could
provide sufficient data without conducting
another study, but that appeal was rejected.
“We are certainly disappointed with this
communication from the FDA. Diabetic
retinopathy is a significant unmet medical
need to which we have devoted more than a
decade of clinical research with no guarantee
of approval.We still believe that ruboxistaurin
has potential as a treatment for diabetic eye
disease and are exploring the feasibility of
further development of this molecule,” said
Dr John Lechleiter, president and chief
operating officer of Eli Lilly and Company, in a
media release.
Lloyd P Aiello MD, Harvard University, was
the director of the PKC DR2 study. He told
EuroTimes that he believes Lilly will support
getting this drug to market in some manner
for the benefit of patients. He commented
that based on the current study results, the
drug does look promising, and that he would
like to see the research continue. He
emphasised that the safety of the drug
appeared to be excellent.
One scenario is that the FDA would
require Lilly to conduct an additional threeyear clinical study.This would literally cost
millions of dollars.The company has not
announced that they will not support such an
investment, but neither have they said that
they would. Even with the best possible
scenario, a large clinical study that produced
significant evidence of therapeutic benefit, the
drug would not come to market for at least
five years.
These recent developments also would
push back the approval of ruboxistaurin in
Europe. Lilly announced it would withdraw its
marketing application from the European
Medicines Agency (EMEA) for the drug.The
EMEA's Committee for Medicinal Products
for Human Use (CHMP) had also asked for
additional data.
Two phase III studies and one phase II
study are under way in the US at present.
Two of these are looking at the effects of
treatment on diabetic macular oedema in
patients with Type 1 and Type 2 diabetes.The
third trial is designed to measure the effects
of treatment on early diabetic kidney in
patients with Type 1 diabetes.
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